The increased prevalence of HIV infection among pregnant women results in an increased need for intervention strategies to reduce vertical transmission to their newborns. It is believed that many infants may become HIV-infected near birth, by contact with virus on their mucosal surfaces. Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a practical animal model of human pediatric aids. We have previously shown that intravenous inoculation of newborn rhesus macaques with uncloned SIVMAC results in rapid virus replication, weak antiviral immune responses and rapid development of disease (most animals died with saids within three months). In the current study, we demonstrate that newborn macaques can be readily infected by uncloned sivmac following oral- conjunctival mucosal exposure, resulting in a similarly rapid disease course. In contrast, when three adult female macaques were vaccinated against SIV during pregnancy (by perivaginal immunization with the nonpathogenic molecular clone SIVMAC1a11 during the second trimester, followed by an intramuscular boost with inactivated whole virus during the third trimester), two of the three newborns were protected against SIV infection following mucosal exposure at birth. These results suggest that intervention strategies, such as active immunization of HIV-infected pregnant women and/or anti-HIV immunoglobulin administration, may decrease the rate of perinatal HIV infection.